This application is a 371 of PCT/JP99/07398, filed Dec. 28, 1999.
The present invention relates to novel 2-oxoquinoline compounds and pharmaceutical uses thereof. In addition, the invention relates to novel uses of some types of 2-oxoquinoline compounds. More specifically, the invention relates to novel 2-oxoquinoline compounds that selectively act on cannabinoid receptors, particularly on peripheral cannabinoid receptors, and that have immunomodulating action, anti-inflammatory action, and antiallergic action with fewer side effects on the central nervous system and to pharmaceutical uses thereof.
So far, a series of compounds named cannabinoids, which comprise C, H, and O, are known as constituents of cannabis. It has also been known that, among them, tetrahydrocannabinol (THC) is a major hallucinogen, and that a principal ingredient contained in the cannabis plant is xcex949-THC. It has been reported that xcex949-THC has actions including ataxia, increased sensitivity to stimulation, antiemetic action, analgesic action, hypothermic action, respiratory depression, catalepsy-inducing action, vasodilator action, immunosuppressive action, etc.
The sites of these actions of xcex949-THC are roughly categorized into the central nervous system (Devane et al., Mol Pharmacol. 1988, 34, 605-613; Hollister et al., Pharmacol. Rev., 1986, 38, 1-20; Renu et al., Prog. Drug Res., 1991, 36, 71-114) and the peripheral tissues (Nye et al., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., Mol Pharmacol. 1992, 41, 736-742). There are reports suggesting that some of the actions on the central nervous system are medically applicable.
On the other hand, it has been found that there exists the peripheral type receptor, for example, the receptor on macrophages (Munnro et al., Nature, 1993, 365, 61-65). Based on this finding, research and development are being carried out with the objective of designing peripheral type receptor agonists capable of modulating immune reaction and having anti-inflammatory action, antiallergic action, as well as the original immunomodulating action.
Further, agents selectively acting on peripheral type cannabinoid receptors can be safe agents that have no side effects on the central nervous system such as hypothermic action, catalepsy, and such, and therefore modulators selective for the peripheral type receptor are expected to be developed in particular.
Known cannabinoid receptor agonists include pyrazole derivatives (Unexamined Published Japanese Patent Application (JP-A) No. Hei 6-73014; EP Nos. 656354 and 658546), THC derivatives (JP-A Hei 3-209377), benzoxazine derivatives (U.S. Pat. No. 5,112,820), indole derivatives (U.S. Pat. No. 5,081,122), and aliphatic acid derivatives (WO 94/12466). However, there have previously been no findings on 2-oxoquinoline compounds by which the compounds of the present invention are characterized.
On the other hand, a variety of quinoline derivatives have been reported in terms of chemical structure.
For example, a reference of J. Pharm. Sci., 73, 11, 1652-1653 (1984) describes 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid benzylamide (compound A shown below), which is useful as a stimulant for the central nervous system. Another reference, Khim. Geterotsikl. Soedin., 8, 1101-1104 (1993), describes 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (pyridine-2-yl)amide (compound B shown below), which is useful as an anti-inflammatory agent. In Pharmaproject and others, it has been reported that 4-hydroxy-2-oxo-1-methyl-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide (compound C shown below) that is also called xe2x80x9croquinimexxe2x80x9d can be used as agents for a variety of diseases, e.g., anti-inflammatory agent, immunosuppressant, and antirheumatic agent.
Further, Examined Japanese Patent Publication No. Sho 47-14107 discloses a method for synthesizing 3-benzoylamino-6,7-dimethoxy-2-(1H)quinolone (compound D shown below) that can be used as an agent acting on the central nervous system.

 
In addition, 2-oxo-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide has been disclosed in Synthesis, 11, 1362-1364 (1995). Quinoline compounds which are useful as immunomodulators have been disclosed in Published Japanese Translation of International Publication No. Hei 4-500373. Quinoline compounds which are useful as analgesic agents have been disclosed in French Patent Publication No. 2377400. Quinoline compounds which are useful as 5-HT4 receptor agonists have been disclosed in republished patent publication WO 96/05166.
Further, one of 2-oxoquinoline compounds having 3,4-methylenedioxyphenyl group, which is one of specific features of the compounds of the present invention, is N-(3,4-methylenedioxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide (compound E shown below), which is a compound capable of enhancing immunological activities and has been disclosed in JP-A Sho 57-171975 (EP No. 59698). Yet further, 1-methyl-2-oxo-3-{N-(1,3-benzodioxole-5-yl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline (compound F shown below), which has immunomodulating action, anti-inflammatory action, and analgesic action, has been disclosed in Published Japanese Translation of International Publication No. Hei 6-506925 (WO 92/18483).
However, these references have no description suggesting the existence of 2-oxoquinoline compounds of the present invention nor suggestion of pharmacological action based on the cannabinoid receptor-mediated mechanism.

 
On the other hand, description found in the publication of WO 97/29079 is that some compounds having quinoline structure, functioning as cannabinoid receptor agonist or antagonist, are useful as immunomodulators, anti-inflammatory agents, antiallergic agents, or the like.
However, the quinoline compounds disclosed in the reference are merely quinolines that have been substituted with a hydroxy, and in the reference, there is no description suggesting the existence of the 2-oxoquinoline compounds of the present invention.
A reference of JP-A Hei 11-80124 (WO 99/02499) also describes immunomodulator, anti-inflammatory agent, and antiallergic agent comprising cannabinoid receptor agonist or antagonist as an active ingredient. The patent publication has also disclosed 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminophenyl)amide (compound G) and such, which is one of compounds having the 2-oxoquinoline structure that is one of specific features of the compounds of the present invention.

 
In more detail, in the above-mentioned patent publication, for example, just merely the above-mentioned compound G and three other compounds are specifically disclosed, and the reference has no description of the inventive compounds that disclosed herein, which is represented by general formula (I), including compounds of which Ra is alkyl; compounds of which X is xe2x80x94COORb, xe2x80x94CONH2, xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)sxe2x80x94R, xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OH, or xe2x80x94(CH2)qxe2x80x94NReRexe2x80x2 (where each symbol is as defined herein); compounds of which X is xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R and Rc is alkyl; or compounds of which R is represented by:

 
where each symbol is as defined herein.
It should be noted that, while the above-mentioned patent application was first laid open to public inspection on Jan. 21, 1999 (WO 99/02499), the priority date of the present application is Jan. 8, 1999, which is therefore earlier than the above publication date.
An objective of the present invention is to provide novel compounds selectively acting on cannabinoid receptors, particularly on peripheral cannabinoid receptors and to provide pharmaceutical compositions thereof.
More specifically, the objective of the present invention is to provide novel compounds and pharmaceutical compositions thereof that are capable of selectively acting on cannabinoid receptors, particularly on the receptors of peripheral tissues, and that have therapeutic effects including immunomodulating action, anti-inflammatory action, antiallergic action, and such, but that hardly influence the central nervous system (specifically, side effects such as excitation, hallucination, ataxia, increased sensitivity to stimulation, hypothermicaction, respiratory depression, catalepsy-inducing action, hypotention, etc.) and that are less toxic.
In order to achieve the above-mentioned objective, the present inventors strenuously studied and then found 2-oxoquinoline compounds exhibiting selective affinity for cannabinoid receptors, particularly for the peripheral type receptors, and thus being pharmaceutically useful for diseases associated with cannabinoid receptors, particularly diseases associated with peripheral type tissues (immune disease, various types of inflammation, allergic diseases, etc.). Thus, the inventors completed the present invention.
Specifically, the present invention comprises the following items (1)-(27):
(1) A cannabinoid receptor modulator comprising, as an active ingredient, a 2-oxoquinoline compound represented by the following general formula [I] or its pharmaceutically acceptable salt:

 
where W means xe2x80x94Oxe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94CR3R4xe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94NR5COxe2x80x94, xe2x80x94CONR5xe2x80x94, xe2x80x94COOxe2x80x94, or xe2x80x94OCOxe2x80x94 (where R3 and R4 may be identical or different and represent hydrogen atom or alkyl; R5 represents hydrogen atom or alkyl; and t indicates an integer, 0, 1 or 2);
R1 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; each group of R1, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl; each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
R2 represents hydrogen atom, alkyl, xe2x80x94OR6 (where R6 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), xe2x80x94NR7R8 (where R7 and R8 may be identical or different and represent hydrogen atom, alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; or R7 and R8, together with the adjacent nitrogen atom, can form a heteroaryl); or xe2x80x94(CH2)uxe2x80x2xe2x80x94S(O)uR9 (where R9 represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and uxe2x80x2 independently represents an integer, 0, 1 or 2); each group of R2, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
Ra represents hydrogen atom or alkyl;
X represents xe2x80x94COORb, xe2x80x94CONH2, xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)axe2x80x94R, xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OH or xe2x80x94(CH2)qxe2x80x94NReRexe2x80x2, (where each of Rb, Rc, Rd, and Rf independently represents hydrogen atom or alkyl; each of Re and Rexe2x80x2 independently represents hydrogen atom or alkyl; or Re and Rexe2x80x2, together with the adjacent nitrogen atom, can form a heteroaryl;
each of AlkaAlkb and Alkc independently represents alkylene or alkenylene; each of the alkylene and alkenylene may be substituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl, alkyl (the alkyl may be substituted or unsubstituted with hydroxy, alkoxy or alkylthio) or xe2x80x94CONR10R11 (where R10 and R11 may be identical or different and represent hydrogen atom or alkyl; or R10 and R11, together with the adjacent nitrogen atom, can form a heteroaryl);
R represents aryl, heteroaryl, cycloalkyl, benzene-condensed cycloalkyl or

 
where A and B independently represent oxygen atom, nitrogen atom or sulfur atom; k indicates an integer of 1-3; each of the aryl and heteroaryl may be substituted or unsubstituted with an alkyl substituted or unsubstituted with hydroxy or may be substituted or unsubstituted with a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronic acid residue; the cycloalkyl may be substituted or unsubstituted with a hydroxy, alkoxy or xe2x95x90O; the benzene-condensed cycloalkyl may be substituted or unsubstituted with a hydroxy or alkoxy; each of r, s, v and w independently represents 0 or 1; each of Y and Z independently represents a nitrogen atom, oxygen atom or sulfur atom; and each of p and q independently represents an integer of 1-4).
(2) A cannabinoid receptor modulator comprising, as an active ingredient, the 2-oxoquinoline compound of (1) or its pharmaceutically acceptable salt, wherein W represents xe2x80x94Oxe2x80x94; R1 is hydrogen atom or alkyl (the alkyl is as described above); R2 represents xe2x80x94OR6 (R6 is as described above); and R is aryl, heteroaryl or

 
where aryl, heteroaryl, and each symbol in the formula are as defined above.
(3) A 2-oxoquinoline compound as represented by the following general formula [Ixe2x80x2] or its pharmaceutically acceptable salt:

 
where W means xe2x80x94Oxe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94CR3R4xe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94NR5COxe2x80x94, xe2x80x94CONR5xe2x80x94, xe2x80x94COOxe2x80x94 or xe2x80x94OCOxe2x80x94 (where R3 and R4 may be identical or different and represent hydrogen atom or alkyl; R5 represents hydrogen atom or alkyl; and t indicates an integer, 0, 1 or 2);
R1 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; each group of R1, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl; each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
R2 represents hydrogen atom, alkyl, xe2x80x94OR6 (where R6 represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), xe2x80x94NR7R8 (where R7 and R8 may be identical or different and represent hydrogen atom, alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; or R7 and R9, together with the adjacent nitrogen atom, can form a heteroaryl); or xe2x80x94(CH2)uxe2x80x2xe2x80x94S(O)uR9 (where R9 represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and uxe2x80x2 independently represents an integer, 0, 1 or 2); each group of R2, except hydrogen atom, may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; each group, except hydrogen atom and alkyl, may be substituted or unsubstituted with alkyl;
Ra represents hydrogen atom or alkyl;
Xxe2x80x2 represents xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)sxe2x80x94R or xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R,
where each of Rc, Rd, Re and Rf independently represents hydrogen atom or alkyl;
each of Alka, Alkb and Alkc independently represents alkylene or alkenylene; each of the alkylene and alkenylene may be substituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl, alkyl (the alkyl may be substituted or unsubstituted with a hydroxy, alkoxy or alkylthio);
or xe2x80x94CONR10R11 (where R10 and R11 may be identical or different and represent hydrogen atom or alkyl; or R10 and R11, together with the adjacent nitrogen atom, can form a heteroaryl);
R represents aryl, heteroaryl, cycloalkyl, benzene-condensed cycloalkyl or

 
where A and B independently represent oxygen atom, nitrogen atom or sulfur atom; k indicates an integer of 1-3; each of the aryl and heteroaryl may be substituted or unsubstituted with an alkyl substituted or unsubstituted with hydroxy or may be substituted or unsubstituted with a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronic acid residue; the cycloalkyl may be substituted or unsubstituted with a hydroxy, alkoxy or xe2x95x90O; the benzene-condensed cycloalkyl may be substituted or unsubstituted with a hydroxy or alkoxy; each of r, s, v and w independently represents 0 or 1; each of Y and Z independently represents a nitrogen atom, oxygen atom or sulfur atom; and each of p and q independently represents an integer of 1-4, provided that;
(a) when R2 is a hydrogen atom, then WR1 is substituted at position-j of 2-oxoquinoline; and
(b) 1,2-dihydro-6,7-dimethoxy-2-oxo-N-(phenylmethyl)-3-quinolinecarboxamide and N-(1,2-dihydro-6,7-dimethoxy-2-oxo-3-quinolyl)benzamide are excluded.
(4) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein Ra is alkyl.
(5) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein Xxe2x80x2 is xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R.
(6) The 2-oxoquinoline compound of (5) or its pharmaceutically acceptable salt, wherein Rc is alkyl.
(7) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein Xxe2x80x2 is xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)sxe2x80x94R or xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R.
(8) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein W is xe2x80x94Oxe2x80x94; R1 is hydrogen atom or alkyl having 1-3 carbons (the alkyl may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl); and R2 is xe2x80x94OR6 (where R6 represents hydrogen atom or alkyl having 1-3 carbons (the alkyl may be substituted or unsubstituted with alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl)).
(9) The 2-oxoquinoline compound of any one of (3)-(8) or its pharmaceutically acceptable salt, wherein R is aryl, heteroaryl or

 
where aryl, heteroaryl, and each symbol in the formula are as defined above.
(10) The 2-oxoquinoline compound of any one of (3)-(8) or its pharmaceutically acceptable salt, wherein R is

 
where each symbol is as defined above.
(11) The 2-oxoquinoline compound of any one of (3)-(10) or its pharmaceutically acceptable salt, wherein W is xe2x80x94Oxe2x80x94 and R2 is xe2x80x94OR6 (where R6 is a hydrogen atom or alkyl)
(12) The 2-oxoquinoline compound of any one of (3)-(11) or its pharmaceutically acceptable salt, wherein the substitution position of WR1 is position-j of the benzene ring, and the substitution position of R2 is position-i of the benzene ring.
(13) The 2-oxoquinoline compound of any one of (3)-(6) and (8)-(12) or its pharmaceutically acceptable salt, wherein Alka is alkylene and r=1.
(14) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound excludes 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide; 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminobenzyl)amide; 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-aminophenyl)ethyl]amide; and 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminophenyl)amide.
(15) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound excludes compounds in which W is xe2x80x94Oxe2x80x94; R1 is alkyl; R2 is xe2x80x94OR6 (where R6 is alkyl); Ra is hydrogen; and Xxe2x80x2 is xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R (where Rc is a hydrogen atom; Alka is methylene, ethylene or trimethylene; r is 0 or 1; and R is aryl or heteroaryl).
(16) The 2-oxoquinoline compound of (5) or its pharmaceutically acceptable salt, wherein R is aryl (the aryl may be substituted or unsubstituted with hydroxy, alkoxy, alkenyloxy, acyloxy, halogen atom, aralkyloxy, or glucuronic acid residue).
(17) The 2-oxoquinoline compound of (3) or its pharmaceutically acceptable salt, wherein R is aryl except phenyl or is heteroaryl except pyridyl.
(18) The 2-oxoquinoline compound of any one of (3)-(17) or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound is selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide (Example 3-1); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminobenzyl)amide (Example 3-2); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-aminophenyl)ethyl]amide (Example 3-3); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminophenyl)amide hydrochloride (Example 3-4); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-5); 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide (Example 3-6); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide (Example 3-7); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-8); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-pyridyl methyl)amide (Example 3-9); 7-methoxy-2-oxo-S-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-piperidinoethyl)amide (Example 3-10); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide (Example 3-11); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3-pyridylmethyl)amide (Example 3-12); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridylmethyl)amide (Example 3-13); 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide (Example 3-14); 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-15); 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide (Example 3-16); 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide hydrochloride (Example 3-17); 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-18); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(2-fluorophenyl)ethyl]amide (Example 3-19); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(3-fluorophenyl)ethyl]amide (Example 3-20); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxy-3-methoxyphenyl)ethyl]amide (Example 3-21); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-chlorophenyl)ethyl]amide (Example 3-22); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide (Example 3-23); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-methylbenzyl)amide (Example 3-24); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-fluorobenzyl)amide (Example 3-25); 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide (Example 3-26); 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-27); 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide (Example 3-28), 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-29); 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide (Example 3-30); 7,8-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-31); 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-32); 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-33); 7-methoxy-2-oxo-6-pentyloxy-l,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide (Example 3-34); 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-35); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-36); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide (Example 3-37); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide (Example 3-38); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-pyridylmethyl)amide (Example 3-39); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-fluorobenzyl)amide (Example 3-40); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide (Example 3-41); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-42); 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-43); 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide (Example 3-44); 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-45), 7,8-dipentyloxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 3-46); 8-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyphenyl)amide (Example 3-47); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-dihydroxybenzyl)amide (Example 3-48); 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-hydroxy-3-methoxybenzyl)amide (Example 3-49); 1-O-{2-hydroxy-5-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylamino methyl]phenyl}glucosidouronic acid and 1-O-{2-hydroxy-4-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylamino methyl]phenyl}glucosidouronic acid (Example 3-50); 5-[7-methoxy-3-{(3,4-methylenedioxybenzyl)carbamoyl)-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoic acid (Example 3-51); 5-[7-methoxy-3-{(3-hydroxy-4-methoxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoic acid (Example 3-52); 8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-53); 8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (4-hydroxy-3-methoxybenzyl)amide (Example 3-54); 8-(4-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-55); 7-methoxy-2-oxo-8-(4-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-56); 8-(3-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-57); 7-methoxy-2-oxo-8-(3-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-58); 8-(2-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (Example 3-59); 7,8-dihydroxy-2-oxo-l,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide (Example 4-1); 8-butoxy-3-hydroxy methyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 5-1); 8-ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 5-2); N-(4-fluorophenyl)carbamic acid (8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl ester (Example 6-1); N-pyridine-4-ylcarbamic acid (8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl ester (Example 6-2); 3-dimethyl aminomethyl-8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 7-1); 8-butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 7-2); 8-ethoxy-7-methoxy-3-morpholinomethyl-2-oxo-1,2-dihydroquinoline (Example 7-3); N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl]-Nxe2x80x2-(4-fluorophenyl)urea (Example 8-1) and N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl]-(4-hydroxyphenyl)acetamide (Example 8-2).
(19) A 2-oxoquinoline compound or its pharmaceutically acceptable salt, the 2-oxoquinoline compound being selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-1); 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-2); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-3); and 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (Example 1-4).
(20) A 2-oxoquinoline compound or its pharmaceutically acceptable salt, the 2-oxoquinoline compound being selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (Example 2-1); 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (Example 2-2); 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (Example 2-3); 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (Example 2-4); 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (Example 2-5); 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (Example 2-6); and 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (Example 2-7).
(21) 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide (Example 3-60) or its pharmaceutically acceptable salt.
(22) A pharmaceutical composition comprising, as an active ingredient, the 2-oxoquinoline compound of any one of (3)-(21) or its pharmaceutically acceptable salt.
(23) A cannabinoid receptor modulator comprising, as an active ingredient, the 2-oxoquinoline compound of any one of (3)-(21) or its pharmaceutically acceptable salt.
(24) A peripheral cannabinoid receptor modulator comprising, as an active ingredient, the 2-oxoquinoline compound of any one of (3)-(21) or its pharmaceutically acceptable salt, the 2-oxoquinoline compound selectively acting on peripheral type cannabinoid receptors.
(25) The 2-oxoquinoline compound of any one of (3)-(21) or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound is an immunomodulator, therapeutic agent for autoimmune diseases, antiallergic agent, or antiinflammatory agent.
(26) The 2-oxoquinoline compound of any of (3)-(21) or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound is an antiinflammatory agent.
(27) An antiinflammatory agent comprising, as an active ingredient, the 2-oxoquinoline compound of (1) or (2) or its pharmaceutically acceptable salt.
Terminologies used herein are defined as follows:
The term xe2x80x9calkylxe2x80x9d means group having 1-10 carbon atoms, which may be linear or branched, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, neohexyl, heptyl, etc.
The group in R2, R2xe2x80x2, R5, and R6 preferably contains 1-7 carbon atoms; more preferred in R6 is a linear alkyl containing 1-6 carbon atoms and still more preferred in R6 is methyl. Preferably, the group in R3 and R4 has 1-4 carbon atoms. The group in R1, R7, R8 and R9 is preferably a linear alkyl having 1-6 carbon atoms; more preferred is ethyl, propyl, butyl or pentyl; till more preferred is propyl, butyl or pentyl; and particularly preferred is pentyl. The group in R10, R11, R12 and R13 preferably has 1-4 carbon atoms; preferred in Ra, Rb, Rc, Rd, Re, Rexe2x80x2 and Rf is 1-4 carbon atoms; and more preferred is methyl.
The term xe2x80x9calkenylxe2x80x9d means the linear or branched group having 2-10 carbon atoms, and is specifically exemplified by vinyl, allyl, crotyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, heptenyl, etc.
The group in R6, R7, R8 and R9 preferably contains 2-7 carbon atoms. Preferably R1 contains 4-7 carbon atoms.
The term xe2x80x9calkynylxe2x80x9d means a linear or branched group having 2-10 carbon atoms, and is specifically exemplified by ethynyl, propynyl, butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, hepynyl, etc.
The group in R6, R7, R8 and R9 preferably contains 2-7 carbon atoms. Preferably R1 contains 4-7 carbon atoms.
The xe2x80x9calkylenexe2x80x9d in Alka, Alkb and Alkc means a linear or branched chain having 1-4 carbon atoms, which is specifically exemplified by methylene, ethylene, trimethylene, tetramethylene, etc., and more preferred is methylene or ethylene. Particularly preferred is methylene for Alka; and particularly preferred is methylene for each of Alkb and Alkc.
The xe2x80x9calkenylenexe2x80x9d in Alka, Alkb and Alkc means a linear or branched chain having 2-4 carbon atoms, which is specifically exemplified by vinylene, propenylene, butenylene, etc.
The term xe2x80x9calkoxyxe2x80x9d means the group of which alkyl portion corresponds to that having 1-4 carbon atoms among the above-defined alkyl groups, which is specifically exemplified by methoxy, ethoxy, propoxy, iospropyloxy, butyloxy, t-butyloxy, etc.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated monocyclic alkyl having 3-8 carbon atoms, which is specifically exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
Preferably the group in R1, R6, R7 and R8 contains 3-6 carbon atoms; preferably R contains 3-7 carbon atoms and particularly preferred is cyclohexyl.
The xe2x80x9ccycloalkylalkylxe2x80x9d in R1, R6, R7 and R8 means the group in which the cycloalkyl portion is the above-defined cycloalkyl containing 3-6 carbon atoms and the alkyl portion is the above-defined alkyl containing 1-4 carbon atoms. Specifically, the group is exemplified by cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, etc.
The xe2x80x9carylxe2x80x9d in R1, R6, R7, R8 and R means an aromatic hydrocarbon having 6-16 carbon atoms and is specifically exemplified by phenyl, naphthyl, biphenyl, anthracenyl, indenyl, azulenyl, fluorenyl, phenanthrenyl, pyrenyl, etc.; preferred is phenyl or naphthyl; and particularly preferred is phenyl.
The xe2x80x9carylalkylxe2x80x9d in R1, R6, R7, R8, R12 and R13 means the group in which the aryl portion corresponds to the above-defined aryl and the alkyl portion is the above-defined alkyl having 1-4 carbon atoms. Specifically, the group is exemplified by benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, biphenylmethyl, etc.; and preferred is benzyl.
The xe2x80x9cheteroarylxe2x80x9d in R1, R6, R7, R8 and R may be saturated or unsaturated with hydrogen atom and is specifically exemplified by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, azepinyl, benzopyranyl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, 1,7-naphthyridyl, 1,6-naphthyridyl, 1,5-naphthyridyl, pyrido[2,3-d]pyrimidyl, thieno[2,3-b]pyridyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholyl, hydroazepinyl, hydroindolyl, hydroisoindolyl, hydroquinolyl, hydroisoquinolyl, etc; preferred is pyridyl, thienyl, piperidyl, piperidino, imidazolyl, or morpholyl; more preferred is pyridyl, piperidyl, or morpholyl; and particularly preferred is pyridyl.
The expression, Re and Rexe2x80x2 xe2x80x9ctogether with the adjacent nitrogen atom, form a heteroaryl,xe2x80x9d means a heteroaryl having one or more nitrogen atoms among above heteroaryl groups; specifically, the group includes pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, morpholino, pyrazolyl, imidazolyl, tetrazolyl, triazolyl, pyrrolyl, pyrrolinyl, indolyl, hydroazepinyl, hydroindolyl, hydroisoindolyl, hydroquinolyl, hydroisoquinolyl, etc.; preferred is morpholino, piperidino or piperazinyl; and particularly preferred is morpholino.
The expression, R7 and R8, or R10 and R11, xe2x80x9ctogether with the adjacent nitrogen atom, form a heteroarylxe2x80x9d has the same meaning as the above-defined expression, Re and Rexe2x80x2 xe2x80x9ctogether with the adjacent nitrogen atom, form a heteroaryl.xe2x80x9d
The xe2x80x9cheteroarylalkylxe2x80x9d in R1, R6, R7, and R8 means the group in which the heteroaryl portion is the same as the above-defined one and the alkyl portion corresponds to the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by 2-thienylmethyl, 3-furylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-isoquinolylmethyl, etc.; and preferred is 4-pyridylmethyl.
The xe2x80x9cbenzene-condensed cycloalkylxe2x80x9d in R means the group of which cycloalkyl portion is the above-defined cycloalkyl; specifically, the group is exemplified by tetrahydronaphthalene, indan, etc.; and preferred is tetrahydronaphthalene.
The xe2x80x9cacylxe2x80x9d in R7 and R8 means a group in which carbonyl has been substituted with the above-defined alkyl or the above-defined aryl; specifically, the group is exemplified by formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, naphthoyl, etc.
Further, each of substituted or unsubstituted groups may be substituted or unsubstituted with one or more substituents, preferably with 1 or 2 substituents. Groups to be used as the substituents are described below.
The term xe2x80x9chalogen atomxe2x80x9d means fluorine, chlorine, bromine and iodine; and preferred are fluorine and chlorine.
The terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d and xe2x80x9cacylxe2x80x9d indicate the same meanings as the above-defined xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d and xe2x80x9cacyl,xe2x80x9d respectively.
The xe2x80x9calkoxycarbonylxe2x80x9d means the group of which alkyl portion is the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.; and preferred is ethoxycarbonyl.
The xe2x80x9calkylaminoxe2x80x9d means the group of which alkyl portion corresponds to the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, etc.
The xe2x80x9calkylthioxe2x80x9d means the group of which alkyl portion is the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by methylthio, ethylthio, propylthio, butylthio, etc.
The xe2x80x9calkylsulfinylxe2x80x9d means the group of which alkyl portion corresponds to the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.
The xe2x80x9calkylsulfonylxe2x80x9d means the group of which alkyl portion is the above-defined alkyl having 1-4 carbon atoms; specifically, the group is exemplified by methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.
The xe2x80x9calkenyloxyxe2x80x9d means the group of which alkenyl portion corresponds to the above-defined alkyl having 2-4 carbon atoms; specifically, the group is exemplified by ethenyloxy, propenyloxy, butenyloxy, etc.
The xe2x80x9cacyloxyxe2x80x9d means the group of which acyl portion is as defined above and is specifically exemplified by formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.; and preferred is acetyloxy.
The xe2x80x9cacylthioxe2x80x9d means the group of which acyl portion is as defined above and is specifically exemplified by formylthio, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.; and preferred is acetylthio.
The xe2x80x9cacylaminoxe2x80x9d means the group of which acyl portion is as defined above and is specifically exemplified by formylamino, acetylamino, propionylamino, butyrylamino, etc,; and preferred is acetylamino.
The xe2x80x9caralkyloxyxe2x80x9d means the group of which aralkyl portion is the above-defined arylalkyl; and the group is specifically exemplified by benzyloxy, phenethyloxy, phenylpropyloxy, phenylbutyloxy, naphthylmethyloxy, biphenylmethyloxy, etc.
Preferred for Ra is hydrogen atom.
Substitution positions for the pair of WR1 and R2 are selected from the group consisting of position-g, position-h, position-i and position-j of 2-oxoquinoline but the respective substitution positions are different from each other. Preferred combination of the substitution positions is the combination of positions-h and -i, or that of positions-i and -j on the ring of 2-oxoquinoline; particularly preferred is the combination of positions-i and -j. It is preferable that R2 is substituted at position-i.
Preferred for W is xe2x80x94Oxe2x80x94, xe2x80x94S(O)txe2x80x94 or xe2x80x94NR5xe2x80x94; more preferred is xe2x80x94Oxe2x80x94. When W is xe2x80x94S(O)txe2x80x94, then t is preferred to be 0; when W is xe2x80x94NR5xe2x80x94, then it is preferable that R5 is a hydrogen atom.
Preferred for R1 is a hydrogen atom or alkyl; more preferred is alkyl; and particularly preferred is unsubstituted alkyl.
Preferred substituents of alkyl include alkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl and alkylsulfonyl; particularly preferred is hydroxy, carboxy or acyl. Alkyl, which has been substituted with any of hydroxy, carboxy, and acyl, is preferred to have 5 carbon atoms in total.
Specific examples of particularly preferred substituted alkyl include 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 2-oxopentyl, 3-oxopentyl, 4-oxopentyl, and 4-carboxybutyl.
Preferred for R2 are the respective groups except hydrogen atom; specifically, such groups are alkyl, xe2x80x94OR6, xe2x80x94NR7R8 and xe2x80x94(CH2)uxe2x80x2xe2x80x94S(O)uR9 (where each symbol is as defined above); more preferred are xe2x80x94OR6, xe2x80x94NR7R8 and xe2x80x94(CH2)uxe2x80x2xe2x80x94S(O)uR9; and particularly preferred is xe2x80x94OR6.
When R2 is xe2x80x94OR6, then preferred for R6 is hydrogen atom or alkyl; particularly preferred is alkyl. When R2 is xe2x80x94NR7R8, then it is preferable that one of R7 and R8 is hydrogen atom and the other is alkyl. When R2 is xe2x80x94(CH2)uxe2x80x2xe2x80x94S(O)uR9, preferred for uxe2x80x2 and u is 0, and preferred for R9 is alkyl.
Preferred for X are xe2x80x94COORb, xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)sxe2x80x94R, xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R, xe2x80x94(CH2)pxe2x80x94OH and xe2x80x94(CH2)qxe2x80x94NReRexe2x80x2 (where each symbol has the same meaning as defined above); particularly preferred is xe2x80x94COORb or xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R; and more preferred for X and Xxe2x80x2 is xe2x80x94CONRcxe2x80x94(Alka)rxe2x80x94R; in this case, preferred for Rc is hydrogen atom.
When X and Xxe2x80x2 are xe2x80x94(CH2)pxe2x80x94OC(xe2x95x90Y)xe2x80x94NRdxe2x80x94(Alkb)sxe2x80x94R and xe2x80x94(CH2)qxe2x80x94NRexe2x80x94C(xe2x95x90Z)xe2x80x94(NRf)wxe2x80x94(Alkc)vxe2x80x94R, then preferred for Y and Z is oxygen atom; preferred for p and q is 1; preferred for w is 1; preferred for s and v is 0; and preferred for Re, Rd and Rf is hydrogen atom
Preferred for R is aryl, heteroaryl or

 
(where each symbol has the same meaning as defined above); more preferred is

 
In the above general formula, preferred for both A and B is oxygen atom and k is preferably 1.
Preferably, R is unsubstituted or has substituent of alkyl substituted or unsubstituted with hydroxy or of hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronic acid residue; and when R has substituents, then the number of substituents is preferably 1 or 2. More preferred is alkyl that may be substituted or unsubstituted with hydroxy or is a hydroxy, alkoxy, halogen atom or glucuronic acid residue; further preferred is alkyl that may be substituted or unsubstituted with hydroxy or is a hydroxy, alkoxy or halogen atom; particularly preferred is methyl group, hydroxy or methoxy. When R is phenyl group, substitution position(s) of the substituent(s) is preferably located at the 4-position in the case of mono-substitution or the 3- and 4-positions in the case of di-substitution.
Specifically, preferred for R is 4-methylphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-(6-carboxy-3,4,5-trihydroxy-2-pyranyloxy)-4-hydroxyphenyl or 4-(6-carboxy-3,4,5-trihydroxy-2-pyranyloxy)-3-hydroxyphenyl; and particularly preferred are 3,4-dihydroxy phenyl and 4-hydroxy-3-methoxyphenyl.
The xe2x80x9cpharmaceutically acceptable saltxe2x80x9d specifically includes but is not limited to salts of alkaline metals such as sodium salts, potassium salts, cesium salts, etc.; salts of alkaline earth metals such as calcium salts, magnesium salts, and such; organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, and such; salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts of organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and such; salts of amino acids such as arginine salts, aspartates, glutamates, etc.
Diseases associated with the cannabinoid receptor include autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, etc.) and inflammatory diseases (e.g., acute and chronic pancreatites, etc.). Particularly, the inventive compound can preferably be used to treat chronic pancreatitis that is hard to be treated with commonly used anti-inflammatory agents.
The xe2x80x9ccannabinoid receptor modulatorxe2x80x9d means an agent capable of regulating the biological activity of cannabinoid receptors, or an agent capable of regulating the expression of cannabinoid receptors; the former includes agonist, antagonist, inverse agonist, and agent capable of enhancing or reducing the sensitivity of cannabinoid receptors; and the latter includes agents capable of enhancing or suppressing the expression of cannabinoid receptors.
The present invention also includes a variety of isomers, prodrugs, metabolites, hydrates, and solvates of the respective compounds.
The term xe2x80x9cprodrugxe2x80x9d means derivatives of the inventive compounds having chemically or metabolically decomposable groups therein and thus capable of being converted to the original compounds having the inherent drug effects after administered into the living body, and which also includes non-covalent complexes and salts thereof.
Compound [I] can be produced, for example, as follows, but the method is not limited thereto.

 
In this formula, R12 and R13 may be identical or different and represent hydrogen, alkyl, arylalkyl or cyano; other symbols have the same meaning as defined above.
(Step 1)
Shown in this step is a method to obtain compound [3] by nitrating the ortho-position of formyl group on the benzene ring of compound [2].
It is possible to obtain a nitro compound by reacting compound [2] with fuming nitric acid in the presence of concentrated sulfuric acid in a solvent.
Such a solvent includes, for example, ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.; and acid solvents such as acetic acid, acetic anhydride, and such; and preferred is acetic acid.
The reaction temperature is generally xe2x88x9250-200xc2x0 C., and preferably xe2x88x9210-60xc2x0 C. The reaction time is generally 15 minutes-48 hours, preferably 1-8 hours. The resulting nitro compound can further be reacted with an alkyl bromide such as bromopentane, etc. in the presence of a base in an adequate solvent to give compound [3].
The suitable base includes, for example, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, n-butyllithium, s-butyllithium, t-butyllithium, and lithium diisopropylamide; and preferred is potassium carbonate.
The adequate solvent includes, for example, hydrocarbon solvents such as benzene, toluene, xylene, hexane, etc.; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, and such; and preferred is dimethylformamide.
The reaction temperature is generally xe2x88x9210-200xc2x0 C., preferably 0-60xc2x0 C. The reaction time is generally 15 minutes-48 hours, preferably 1-8 hours.
(Step 2)
Compound [4] can be obtained by reducing the nitro group of compound [3] according to a commonly used method.
(Step 3)
Compounds [4] can be condensed with a malonic acid derivative [5] in the presence of an adequate acid or base to give compound [6]. The malonic acid derivative includes, for example, diethyl malonate, dimethyl malonate, dibenzyl malonate, ethyl cyanoacetate, methyl cyanoacetate, and such; and preferred is dimethyl malonate. The adequate acid includes, for example, benzoic acid, p-toluenesulfonic acid, acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and such; benzoic acid is preferably used. The base includes, for example, sodium hydride, potassium t-butoxide, sodium ethoxide, sodium methoxide, ammonium acetate, sodium acetate, piperidine, pyridine, pyrrolidine, n-methylmorpholine, morpholine, triethylamine, and such; and preferred is piperidine.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, xylene, hexane, heptane, etc.; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, etc.; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, etc.; and alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.; and preferred is toluene.
The reaction temperature is generally 0-150xc2x0 C., and preferably 120xc2x0 C. The reaction time is generally 2-48 hours, and preferably 24 hours.
(Step 4)
Compound [6] can be hydrolyzed in the presence of an adequate base in a solvent to give compound [7].
The solvent includes alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, and such; water; or a mixed solvent thereof.
The suitable base includes, for example, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, and such; and preferred is lithium carbonate.
(Step 5)
Compound [7] that has been converted to an activated carboxylic acid derivative is allowed to react to compound [8] to yield compound [I] of interest.
The activated carboxylic acid derivative includes, for example, acid halide that can be obtained by treating carboxylic acid with thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, and such; active ester that can be obtained by condensing carboxylic acid with 1-hydroxybenzotriazole, N-hydroxysuccinimide or the like by using a condensing agent such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride, and such; mixed acid anhydride that can be obtained by reacting carboxylic acid to ethyl chlorocarbonate, pivaloyl chloride, isobutyl chlorocarbonate or the like, and such; preferably used is active ester that can be obtained from N-hydroxybenzotriazole by using EDC hydrochloride as a condensing agent.
If required, it is also possible to use a base in combination in the above reaction.
The base includes, for example, organic amines such as triethylamine, pyridine, and N-methylmorpholine; and preferred is triethylamine.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, and such; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, and such; and preferred is dimethylformamide.
The reaction temperature is generally 0-100xc2x0 C., and preferably 0-50xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.

 
In this formula, Rx represents halogen atom; each of R1xe2x80x2 and R6xe2x80x2 independently represents alkyl; and Rb is as defined above.

 
In this formula, Raxe2x80x2 represents alkyl; R1xe2x80x2, R6xe2x80x2, Rx, Ra and Rb are as defined above.

 
In this formula, R1xe2x80x3 represents alkyl; R1xe2x80x2, R6xe2x80x2, Rx, Ra, Rc, Alka, R and r are as defined above.
(Step 1)
Compound [9] (3,4-dihydroxybenzaldehyde) is allowed to react by using alkylating agent [10] in the presence of a base, thereby selectively alkylating the hydroxyl group located at the 4-position of the phenol of compound [9]. This results in the production of compound (11).
The alkylating agent to be used includes alkyl iodide such as methyl iodide, etc.; alkyl bromide such as methyl bromide, ethyl bromide, propyl bromide, butyl bromide, pentyl bromide, and such; alkyl chloride such as pentyl chloride, and such; dialkyl sulfate such as dimethyl sulfate, and such; and preferably used is alkyl bromide.
The base includes, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, and such; and preferably used is lithium carbonate.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, xylene, hexane, and such; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, and such; alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, and such; and preferably used is dimethylformamide.
The reaction temperature is generally xe2x88x9220-100xc2x0 C., and preferably 0-100xc2x0 C. The reaction time is generally 15 minutes-48 hours, and preferably 1-6 hours.
(Step 2)
Compound [11] can be reacted with fuming nitric acid in the presence of concentrated sulfuric acid in a solvent, thereby mono-nitrating the ortho-position of formyl group of compound [11] to obtain compound [12] (where compound [12] refers to compound [12a], compound [12b] and a mixture thereof).
The solvent includes, for example, ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc.; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; alcohol solvents such as methanol, ethanol, isopropyl alcohol, t-butanol, and such; acid solvents such as acetic acid, acetic anhydride, and such; preferably used is acetic acid.
The reaction temperature is generally xe2x88x9250-200xc2x0 C., and preferably xe2x88x9210-60xc2x0 C.
Alternatively, compound [12] can be obtained by nitrating compounds [11] by using lanthanum nitrate and sodium nitrate in the presence of an acid in a solvent in this step.
The acid includes, for example, benzoic acid, p-toluenesulfonic acid, acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and such; and preferred is hydrochloric acid.
The solvent includes, for example, the above-mentioned solvents and preferred is tetrahydrofuran.
The reaction temperature is generally xe2x88x9250-200xc2x0 C., and preferably 0-50xc2x0 C.
(Step 3)
Compound [12] is allowed to react by using alkylating agent [13] in the presence of a base in a solvent, thereby alkylating the hydroxyl group located in the phenol of compound [12]. This results in the production of compound [14] (which means regioisomers and a mixture thereof corresponding to compound [12]).
The alkylating agent to be used includes the alkylating agents as described in Step 1 of Production method 2; and preferably used is alkyl bromide.
The base includes the bases as described in Step 1 of Production method 2; and preferably used is potassium carbonate.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferably used is dimethylformamide.
The reaction temperature is generally xe2x88x9220-200xc2x0 C., and preferably 0-100xc2x0 C. The reaction time is generally 15 minutes-48 hours, and preferably 1-24 hr.
(Step 4)
Compound [14] is allowed to react to malonic acid in a solvent, thereby dehydration-condensing the formyl group moiety of compound [14]. This results in the production of compound [15] (which means regioisomers and a mixture thereof corresponding to compound [12]).
The solvent includes the solvents as described in Step 2 of Production method 2; and preferred is acetic acid.
The reaction temperature is generally xe2x88x9220-200xc2x0 C., and preferably 0-100xc2x0 C. The reaction time is generally 2-72 hours, but preferred is 3-24 hours.
(Step 5)
Compound [15] is esterified with alkylating agent [16] in the presence of a base in a solvent, thereby protecting the carboxyl group. This reaction results in the production of compound [17] (which means regioisomers and a mixture thereof corresponding to compound [15]).
The alkylating agent includes the alkylating agents as described in Step 1 of Production method 2; and preferred is methyl iodide.
The base includes the bases as described in Step 1 of Production method 2; and preferred is potassium carbonate.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferred is dimethylformamide.
The reaction temperature is generally xe2x88x9220-200xc2x0 C., and preferably 0-50xc2x0 C. The reaction time is generally 15 minutes-48 hours, and preferably 1-24 hours.
(Step 6)
After the nitro group of compound [17] is reduced according to a commonly used method, the compound is condensed to construct the xcex1-quinolone backbone. The reaction results in the production of compound [I-1a], compound [I-1axe2x80x2], or a mixture thereof.
(Step 7)
Compound [I-1a], compound [I-1axe2x80x2], or the mixture thereof, is alkylated by using alkylating agent [18] according to the same method as described in Step 3 of Production method 2. The reaction alkylates the NH portion of the quinolone moiety and this results in the production of the corresponding compound [I-1b], compound [I-1bxe2x80x2] or a mixture thereof.
(Step 8)
The esterified moiety of compound [I-1a], compound [I-1axe2x80x2], compound [I-1b] or compound [I-1bxe2x80x2] is hydrolyzed according to a commonly used method to obtain the corresponding compound [I-2a], compound [I-2axe2x80x2], compound [I-2b] and compound [I-2bxe2x80x2] (these four compounds are combined to be compound [I-2]).
(Step 9)
Compound [I-2], which has been converted to an activated carboxylic acid derivative, can be treated and amide-condensed with compound [8] in a solvent to give compound [I-3].
The activated carboxylic acid derivative includes, for example, acid halide that can be obtained by treating carboxylic acid with thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, and such; active ester that can be obtained by condensing carboxylic acid with 1-hydroxybenzotriazole, N-hydroxy succinimide or the like by using a condensing agent such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) hydrochloride, and such; mixed acid anhydride that can be obtained by reacting carboxylic acid with ethyl chlorocarbonate, pivaloyl chloride, isobutyl chlorocarbonate or the like; and preferably used is active ester obtained from N-hydroxybenzotriazole by using EDC hydrochloride as a condensing agent.
If required, it is also possible to use a base in combination in the above reaction. The base includes, for example, organic amines such as triethylamine, pyridine, and N-methylmorpholine; and preferred is triethylamine.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, and such; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; ester solvents such as ethyl acetate, methyl acetate, butyl acetate, and such; polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.; and preferred is dimethylformamide. The reaction temperature is generally 0-100xc2x0 C., and preferably 0-50xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.
(Step 10)
Compound [I-3] is treated with a Lewis acid in a solvent, thereby dealkylating the ether moiety. This reaction results in the production of compound [I-4].
The Lewis acid includes, for example, titanic tetrachloride, aluminum chloride, aluminum bromide, trimethylsilyl iodide, boron trichloride, boron tribromide, and such; and preferred is boron tribromide. Sulfur compound such as thiophenol, ethyl mercaptan, and such may be used in combination.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, and such; ether solvents such as tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; and preferred is dichloromethane.
The reaction temperature is generally xe2x88x92100-100xc2x0 C., and preferably xe2x88x9280-0xc2x0 C. The reaction time is generally 15 minutes-24 hours, but preferred is 30 minutes-5 hours.
In this production method, it is also possible to obtain compound [I-3] by condensing compound [I-2a], [I-2axe2x80x2] or a mixture thereof with compound [8] in the same manner as described in Step 9 of Production method 2 and then alkylating the NH portion of quinolone backbone in the same manner as described in Step 7 of Production method 2.
Alternatively, it is also possible to obtain compound [I-3], for example, by skipping Step 3, treating compound [12] by using the procedure of Step 4 and later procedures for the ring formation of 7-substituted 8-hydroxy-2-oxoquinoline, then carrying out the procedure of Step 9 for amide-condensation, followed by alkylation by the method of Step 3. Thus, different combinations of the steps can be used for the production.

 
In this formula, each symbol is as described above.
(Step 1) Compound [I-2], which is obtained by Production method 1 or Production method 2, is treated with a reducing agent in a solvent, thereby reducing the carboxyl group of compound [I-2]. Compound [I-5] is obtained by the reaction in this step.
The reducing agent includes common reducing reagents for carboxyl group, such as borane, etc., but it is preferable to use a method in which carboxylic acid is reduced after converted to an activated carbonyl derivative.
The activated carboxylic acid derivative includes, for example, mixed acid anhydride that can be obtained by reacting carboxylic acid to isopropyl chlorocarbonate, ethyl chlorocarbonate, pivaloyl chloride, isobutyl chlorocarbonate or the like; and preferred is an active ester obtained from isopropyl chlorocarbonate.
If required, it is also possible to use a base in combination in the above reaction. The base includes, for example, organic amines such as triethylamine, pyridine, and N-methylmorpholine; and preferred is triethylamine. Used for the reduction of activated carboxylic acid are sodium borohydride, lithium borohydride, and such; and preferred is lithium borohydride.
The solvent includes, for example, hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.; ether solvents such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and such; and preferred is tetrahydrofuran.
In some cases in this reaction, base treatment should be carried out after reduction. The base being used in this reaction includes sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and such; and preferred is sodium hydroxide. The reaction temperature is generally xe2x88x9220-100xc2x0 C., and preferably xe2x88x9210-30xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.
(Step 2)
Compound [I-5] is treated with isocyanate or thioisocyanate compound [20] in the presence of a base in a solvent to give compound [I-6].
The isocyanate and thioisocyanate include, for example, aralkyl isocyanate such as benzylisocyanate, and such; and arylisocyanate such as phenyl isocyanate, 4-fluorophenyl isocyanate, pyridine-4-yl isocyanate, and such; and preferred is arylisocyanate.
The base includes, for example, organic amines such as triethylamine, pyridine, N-methylmorpholine, and such; and preferred is triethylamine.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferred is chloroform.
The reaction temperature is generally xe2x88x9220-100xc2x0 C., and preferably xe2x88x9210-30-C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.
(Step 3)
Compound [I-5] is treated with acid chloride and then with amine compound [21] to give compound [I-7] in the presence of a base in a solvent.
The acid chloride includes methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, and such; and preferred is methanesulfonyl chloride.
The base includes, for example, organic amines such as triethylamine, pyridine, N-methylmorpholine, and such; and preferred is triethylamine.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferred is tetrahydrofuran.
The reaction temperature is generally xe2x88x9220-100xc2x0 C., and preferably xe2x88x9210-30xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.
(Step 4)
When at least Rexe2x80x2 is a hydrogen atom in compound [I-7], compound [I-7] can be subjected to a coupling reaction with isocyanate or thioisocyanate compound [22] in a solvent to give the corresponding compound [I-8].
The isocyanate and thioisocyanate include those described in Step 1 of Production method 3; and preferably used is arylisocyanate.
If required, it is also possible to use a base in combination in the above reaction. The base includes, for example, organic amines such as triethylamine, pyridine, and N-methylmorpholine; and preferred is triethylamine.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferred is dimethylformamide.
The reaction temperature is generally 0-100xc2x0 C., and preferably 0-50xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably 1-12 hours.
(Step 5)
When at least Rexe2x80x2 is a hydrogen atom in compound [I-7], compound [I-7] can be subjected to a coupling reaction with an activated carboxylic acid derivative in a solvent to obtain compound [I-8xe2x80x2].
The carboxylic acid derivative to be used in the coupling reaction using an activated carboxylic acid derivative includes acid halide, active ester, mixed acid anhydride, etc. obtained from carboxylic acid [23] by the procedure as described in Step 9 of Production method 2; and preferred is an active ester obtained from N-hydroxybenzotriazole by using EDC hydrochloride as a condensing agent.
The solvent includes the solvents as described in Step 1 of Production method 2; and preferred is dimethylformamide.
The reaction temperature is generally 0-100xc2x0 C., and preferably 0-50xc2x0 C. The reaction time is generally 15 minutes-24 hours, and preferably is 1-12 hours.
Compound [I] produced in the above-mentioned manner can be separated and purified, for example, by known methods such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, re-crystallization, chromatography and the like.
Further, pharmaceutically acceptable salts of compound [I] and also various isomers of compound [I] can be produced according to previously known methods.
Compound [I] and pharmaceutically acceptable salts thereof exhibit pharmaceutical effects on diseases known to be associated with cannabinoid receptors, particularly diseases associated with peripheral cell tissues (immune disease, various types of inflammation, allergic diseases, etc.) in mammals.
In other words, compound [I] and pharmaceutically acceptable sales thereof selectively act on cannabinoid receptors, particularly on peripheral cannabinoid receptors, and thus have excellent immunomodulating action, anti-inflammatory action and antiallergic action, but exert fewer side effects on the central nervous system.
Thus, compound [I] and pharmaceutically acceptable salts thereof are useful as modulators for cannabinoid receptors (particularly for peripheral cannabinoid receptors), immunomodulators, therapeutic agents for autoimmune diseases, anti-inflammatory agents and antiallergic agents.
When the compound [I] or their pharmaceutically acceptable salts are used as a pharmaceutical composition, they may be formulated into tablets, pills, powders, granules, suppositories, injections, eye drops, liquid, capsules, troaches, aerosols, elixirs, suspensions, emulsions, syrups, and so on by using a standard method, generally together with known pharmacologically acceptable carriers, excipients, diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifiers, aromatizers, colorants, edulcorants, viscosity increasing agents, flavors, solubilizers, or other additives such as water; plant oil; alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose; or carbohydrates such as starch, magnesium stearate, talc, lanolin, vaseline, etc. The composition may be administered orally or parenterally.
The dose depends on the type and condition of disease, the type of compound to be administered and administration route, age, sex, and body weight of patient, etc. In general, compound [I] is daily given to an adult at a dose of 0.1-1000 mg, and preferably 1-300 mg, once or divided in the case of oral administration.
Further, the compounds of the present invention can be used as animal drugs.